Substituted piperidine compounds and methods of their use

Abstract

Novel 3,4-disubstituted-4-aryl-piperidine compounds are disclosed. Pharmaceutical compositions containing the 3,4-disubstituted-4-aryl-piperidine compounds and methods of their pharmaceutical uses are also disclosed. The compounds disclosed are useful, inter alia, as antagonists of opioid receptors.

1. A compound of formula I: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is H or alkyl; 
 R 2a  is alkyl; 
 R 2b  is H, or alkyl; 
 R 3  is H, alkyl,-or aralkyl; 
 R 4  is
 H, or 
 alkyl 
 
 R 5  is —CH 2 P(═O)OR 7b OR 7c ; 
 R 7b , and R 7c  are each independently H, or alkyl 
 m is the integer 0, 1, 2, 3, or 4; 
 or a pharmaceutically acceptable salt thereof. 
 
       
     
     
       2. A compound according to  claim 1 , wherein R 1  is H. 
     
     
       3. A compound according to  claim 1 , wherein R 2a  and R 2b  are trans to each other. 
     
     
       4. A compound according to  claim 1 , of formula II: 
       
         
           
           
               
               
           
         
       
     
     
       5. A compound according to  claim 1 , wherein R 2a  and R 2b  are each methyl. 
     
     
       6. A compound according to  claim 1 , of formula III: 
       
         
           
           
               
               
           
         
         wherein:
 R 3  is aralkyl. 
 
       
     
     
       7. A compound according to  claim 1 , wherein R 3  is: 
       
         
           
           
               
               
           
         
       
     
     
       8. A compound according to  claim 7 , wherein R 1  is H, R 2a  and R 2b  are each methyl and are trans to each other, m is the integer 1, R 4  is H, and R 7b , and R 7c  are each independently H or methyl. 
     
     
       9. A compound according to  claim 5 , wherein R 3  is: 
       
         
           
           
               
               
           
         
       
     
     
       10. A compound according to  claim 4 , wherein R 2a  and R 2b  are each methyl. 
     
     
       11. A compound according to  claim 1 , of formula IX: 
       
         
           
           
               
               
           
         
         wherein:
 R 3  is H, alkyl, or aralkyl. 
 
       
     
     
       12. A compound according to  claim 1 , wherein R 4  is H. 
     
     
       13. A compound according to  claim 1 , wherein m is the integer 1. 
     
     
       14. A pharmaceutical composition, comprising:
 a pharmaceutically acceptable carrier; and 
 an effective amount of a compound according to  claim 1 . 
 
     
     
       15. A pharmaceutical composition according to  claim 14 , further comprising an effective amount of at least one opioid. 
     
     
       16. A pharmaceutical composition according to  claim 15 , wherein said opioid is alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil, tramadol or mixtures thereof. 
     
     
       17. A pharmaceutical composition comprising the compound ({2S-Benzyl -3-[4-(3-hydroxyphenyl)-3R,4R-dimethylpiperidin-l-yl]-propionylamino }-methyl)-phosphonic acid or a pharmaceutically acceptable salt thereof.